Cardiovascular disease remains the leading cause of death in the United States, accounting for over 40% of deaths and more than $394 billion in annual healthcare costs. Anti-platelet therapy is a cornerstone of acute and long-term management of cardiovascular disease, but current anti-platelet regimens do not reliably inhibit platelet activation in all patients leaving sub-groups of patients un-protected from recurrent cardiovascular events. Platelet hyperreactivity is associated with increased risk of coronary events and death from a cardiovascular cause. The risk of cardiac events following percutaneous coronary intervention (PCI) is 16.7% for patients with high baseline platelet reactivity compared to only 1.9% for patients with low platelet reactivity. After myocardial infarction, patients with high residual platelet reactivity have a relative risk of death of 5.9 compared to patients with normal or low platelet reactivity.
Platelet activation is a complex event mediated by a number of factors that are intrinsic and extrinsic to the platelet. Vascular injury stimulates platelet adhesion via activation of platelet glycoproteins. This is followed by platelet activation and by release of chemical mediators such as thrombin, ADP, thromboxane A2, or epinephrine. These platelet activators have two main roles that include recruiting more platelets at the site of the wound and activating the platelets so that the platelets aggregate.
A the endothelium plays a role in the regulation of the platelet reactivity. Endothelial cells produce several factors that influence blood flow, blood coagulation and angiogenesis. These cells metabolize arachidonic acid to produce several prostaglandins, which play a role in the regulation of thrombus formation by modifying the platelet reactivity. Prostacyclin (PGI2) inhibits platelet aggregation and attachment of platelets to the endothelial surface. In the microvasculature in humans, prostaglandin E2 (PGE2) is the major prostaglandin secreted by the endothelial cells. Indeed, in healthy humans both PGI2 and PGE2 play a physiologic role in modulating the coronary response to sympathetic stimulation and their defective production in patients with angina may be responsible for the paradoxical increase in coronary vascular resistance following sympathetic stimulation. However, the role of PGE2 in the progression of atherosclerotic vascular disease and platelet function is not well-understood. In humans it has been observed that the effects of PGE2 on platelet reactivity are not fully consistent, and can significantly differ among individuals in terms of platelet response.
Hence, there remains a need to determine the role of PGE2 on platelet activity on a genetic level. There also remains a need to utilize such genetic information in the diagnosis, prognosis, and treatment associated with a cardiovascular event.